Novel cycloalkanol fumarate ethers and a process for the preparation thereof

ABSTRACT

New cycloalkanol ethers of the general formula   and their salts and quaternary derivatives were prepared.

United States Patent [191 Budai et al.

[451 Sept. 9, 1975 NOVEL CYCLOALKANOL FUMARATE ETHERS AND A PROCESS FOR THE PREPARATION THEREOF [75] Inventors: Zoltan Budai; Laszlo Pallos; Lujza E. Petocz; Ibolya Kosoczky, all of Budapest, Hungary [73] Assignee: Egyt Gyogyszervegyeszeti Gyar,

Budapest, Hungary [22] Filed: July 12, 1972 [21] Appl. No.: 271,001

3,254,083 5/1966 Stach 260/268 R 3,330,831 7/1969 English 260/268 R 3,471,504 10/1969 Satzinger... 260/268 R 3,634,498 l/l972 Satzinger... 260/268 R 3,654,277 4/1972 Winter 260/268 R FOREIGN PATENTS O'R APPLICATIONS 1,209,567 1/ 1966 Germany 260/268 R Primary ExaminerDonald G. Daus [57] ABSTRACT New cycloalkanol ethers of the general formula lam- (C 2), C R4 (I),

and their salts and quaternary derivatives were prepared.

2 Claims, N0 Drawings NOVEL CYCLOALKANOL FUMARATE ETHERS AND A PROCESS FOR THE PREPARATION THEREOF The compounds of the general formula (I) may be converted into their acid addition salts or quaternary derivatives. The obtained stereoisomeric compounds can be transformed into other stereoisomeric forms.

In the above formulas n is an integer of 4 to 7,

m is an integer of to 12,

R stands for hydrogen, phenyl, monohalophenyl or dihalophenyl group,

R stands for hydrogen, C, alkyl, C hydroxyalkyl or trimethoxybenzoyloxy alkyl group,

R", R, R and R are hydrogen, or R and R and/or R and R may represent together a valence bond,

Hal stands for a halogen atom.

The new compounds of the general formula ('1) possess valuable pharmacological properties. Among others, they have spasmolytic, central stimulating and appetite-decreasing effects.

This invention relates to novel cycloalkanol ethers of pharmaceutical effect and to pharmaceutical products containing the same, as well as to processes for the preparation thereof.

The novel compounds of the invention are represented by the general formula n is an integer of 4 to 7,

m is an integer of 0 to 12,

R stands for hydrogen, phenyl, monohalophenyl or dihalophenyl group, I

R stands for hydrogen, C alkyl, C hydroxyalkyl or trimethoxybenzoyloxy alkyl group,

R, R, R and R are hydrogen, or R" and R and/or R and R may represent together a valence bond.

The salts and quaternary derivatives of the above compounds are also novel and fall also under the scope of the invention. The scope claimed encompasses all the possible stereoisomers and isomeric mixtures of the above compounds.

The novel compounds of the general formula (l) can be prepared according to the invention by several methods.

According to the method of the invention, an alcohol of the general formula (prepared eg as described in .I. Am: Chem. Soc. 70, 3352/1948/; Arzneimittelforschung, 12, /1962/. or l. Am. Chem. Soc. 78, l24/l956/), wherein n, m and R have the same meanings as defined above, is reacted in the presence of a basic condensing agent with a propargyl halide of the general formula Hal CH c a CH (m) wherein I-Ial' representsa halogen atom, and the obtained propargyl ether of the general formula wherein n, m and R have the same meanings as defined above, is aminomethylated in the presence of a known piperazine derivative of the general formula HN (V).

wherein Hal represents a halogen atom, and R has the same meanings as indicated above.

As basic condensing agent preferably an alkali metal amide, e.g. sodium amide or an alkali metal hydride, eg, sodium hydridecan be used. The reaction can also be carried out in the presence of an alkali metal condensing agent, in vthis case, however, the reaction time is considerably long.

The propargyl halides of the general formula (III) are preferably the corresponding bromides or chlorides.

Iodides can alsobe used, but their use is less advantageous.

The aminomethylation of the propargyl ethers having the general formula (IV) is preferably carried out-in the presence of aqueous formaldehyde solution of paraformaldehyde.

According toa third process of the invention, a propargyl etherof thegeneral formula (IV), wherein n, m I and R have the same meanings as defined above, is reacted with equivalent amounts of a C alkyl magnesium halide, the obtained compound of the general formula A ((Tli (VII),

wherein n, m, R and Hal have the same meanings as defined above, is reacted with formaldehyde, the obtained compound of the general formula (VIII).

wherein n, m and R have the same meanings as defined above. is converted into its reactive ester derivative, and the obtained reactive ester is aminated with a piperazine derivative of the general formula (V), wherein R has the same meanings as defined above. In this step compounds of the general formula partial hydrogenation of the compounds having the" general formula (IX) can preferably be carried out with hydrogen in the presence of a partially poisoned catalyst. As catalyst, preferably paIladium-on-carbon, partially poisoned with calcium bonate and lead acetate, can be used. The reaction is preferably conducted at room temperature andatmospheric pressure, in the presence ofa solvent. Among the solvents, methanol is the preferred one.

The total hydrogenation of the compounds having the general formula (IX) can preferably be carried out with hydrogen, in the presence of a catalyst. As catalyst, peferably Raney nickel or paIladium-on-carbon can be used.

The compounds of the general formula (I) can be converted into their pharmaceutically acceptable acid addition salts or quaternary derivatives, or the compounds obtained in the form of salts can be converted into the corresponding free bases. The individual stereoisomers of the compounds having the general formula (I) can be transformed into other isomers according to known techniques. E.g., the trans derivatives can be prepared from the corresponding cis compounds by ultraviolet irradiation in a solvent, e.g. in benzene.

The compounds of the gcncralformula (I), as well as their pharmaeeutieally acceptable acid addition salts and quaternary derivatives can be converted into pharmaceutical products according to known techniques. The pharmaceutical products may contain the novel compounds as single active ingredients or together with other biologically active and/or synergistic agents. The pharmaceutical products are prepared by using the carriers and auxiliary substances generally usable for the preparation of such products.

The" compounds of the general formula (I) possess valuable" pharmacological properties. They have a strong effect in inhibiting nicotine spasm and nicotine lethality as well as phenothiazine catalepsy, and they exert a marked stimulating effect on the central nervous system. The novel compounds decrease the appetite to a great extent. They have also moderate antiserotonine, antiperistaltie and caolin oedemainhibiting activities. Some of the novel compounds also inhibit the gastric secretion. Besides their favourable pharmacological properties, the toxicity of the new compounds is extremely low.

The toxicity data of some of the compounds according to the invention 'are listed in Table 1.

Note: The toxicity of the compounds was examined on white mice. The LD values were calculated on the basis of mortality observed within 48 hours.

The data relating to the stimulating effect of the new compounds (measured in motility tests) are summarized in Table 2. As reference compound, amphetamine was used. The tests were carried out on white mice of both sexes, using a Dews-apparatus. The compounds to be tested were administered orally. The increase of motility was expressed by the ED values. ED represents the dose which increases the number of light-interruptions in average to' 300. The average number of light-interruptions observed in the control groups was I00 to 150.

Table 2 Compound (Example No.) ED mg./kg. Therapeutic Index Amphetamine 3.3 7.6 I2 I05 257 I4 5.6 425 I5 300 23.3 22 3.3 7.6

As, it is known from the literature, compounds of stimulating effect show a food-intake inhibiting activity in mice observed in corn-gnawing tests. The results of this test are summarized in Table 3. As reference compound, amphetamine was used.

Table 3 Compound (Example No.) ED mgJkg. p.o. Therapeutic Index Amphetamine 2.8 8.9 I2 I2.() 22.5 14 39.0 6.]

5 6 The above compounds show stimulating and food- Table 7 intake inhibiting activities also in rats. 7

The novel c m o ds h a ti hyperten Compound Method ot'ad- Dose causing l5 '7: increase sive action on narcotized cats, the degree of which de- NM m'mstmmn m Slccpmg pcrmd pends on the actual sympathic tonus of the animals. 5 1 .0. 30 The compounds potentiate also the pressor activity of t;

noradrenaline. I

Habituation (i.e. decrease in the motility-increasing activity) was not observed, when the compounds were administered orally into white mice for 3 weeks.

Some of the novel compounds show inhibiting activity in motility tests. The doses of compounds inhibiting In the anticonvulsive tests, the compounds showed 1 measurable activity only against nicotine in white mice.

The results are The in Table 8. the data refer to the socalled tonus-convulsions.

the motility in 5() 7r are listed in Table 4. Table 8 l5 w y 1 I Com- Dose Method of ad-. Inhibition. 7: pound T ble 4 (Example mg./kg. ministration Nicotine Nicotine No.) I convulsions lethality Dose causing I I 7 Compound 50 92 inhibition Method of ad- 20 (Example No.) mg/kg. ministration l3 14 ll) 1.0. 0 (l 1 1 33 i.p. 15 a 1x 30 i. I 1x 30 I i.p. ,50 I .60 7 3o l7 30 i.p. 1 4t) 48 5 L 19 BO i.p. '58 64 2] 2-70 PM 20 40 37 23 200 Lp 6O (ill 22 3o i.p. o 0 I6 30 i.p. 20 20 I 21 30 i.p. 1011 The spasmolytic activity of water-soluble compounds 30 was investigated on isolated rat ileum, according to the The a ti i fl t i i fth compounds was Magnus m thod Th results ar st in Tablc 5 investigated on rats, in kaolin edema test. The results are summarized in Table 9.

Table 9 Table 5 Compound Dose Method of ad- Inhibition '7: Compound Activity related to that of 7 (Example N0) ml'mstmmm (Example No.) papaverine (=l l I8 30 LP 2-3 18 15 i.p. 114.4 I l 40 17 30 i.p. 37.11 13 17 15 i.p. 19.0 13 0.5a 1 2o 3o i.p. 24.5 14 I g (1.93 20 15 i.p. 19.0 15 1.22 23 200 i.p. 22.0 3 v f, 1 22 6i) i.p. 28.0

.16 5 '1 I I 1 lp 1811 The antiserotonine activity was investigated on white The spasmolytic activity of water-insoluble com mice, using the Wooley method. The results measured pounds was investigated on white mice. using the Stickon the active compounds are listedin Table I0. ney method. The results of this test, as well as the toxic- I ity data of the compounds related to papaverine are Table I0 summarized in Table 6.

Compound (Example No.) 7 ED, mgJkg. i.p. Table 6 22 about 5t) Compound Method ofaddose Inhibition Rel. toxi Ink/kg It is to be ment1oned that compounds havlng no st1m- '8 a 30 47 054 ulatlng effect. or possessing even a sedative activity. 17 $.L'. 3o 32 (1.68 also decrease the appet1te of the test anlmals, as shown 19 M I 30 2: 11.47 by the data of Table 1 1. 2H s.e. 3U 34 (L68 The examinations were carried out on Vistar rats. by

Papaverine se (12.5 1.00

the Spenglcr-Waser method. The compounds to be I pound. chlorphentermine was used. The result was The data relating to the evipan-narcosis stimulating considered positive, if the food! intake was lower than effect of some compounds are listed in Table 7. 5 g. during the 2 hours of examination. 5

tested were administered orally. As reference com-- As it turns out from the above data, the ED values of the examined two new compounds are about 3.5 and times higher, respectively, than that of chlorphentermine. It is to be mentioned, however, that the toxicity of the novel compounds is about 5.5 and 12 times lower, respectively, than that of the reference compound.

Finally it is to be mentioned that the end-product of Example 21 inhibits the gastric secretionin rats operated by the technique of Shay after 3 hours of pretreatment. The compound was administered in an oral dose of 100 mg./kg. The results are shown in Table 12.

The invention is further elucidated by the aid of the following, non-limiting Examples.

EXAMPLE 1 l-Dodecyll 3 -propargyloxy )-cyclohexane 7.8 g. (0.2 moles) of finely powdered sodium amide and 60 ml. of abs. benzene are introduced into a 500 ml. three-necked flask equipped with a stirrer, addition funnell and reflux condenser. The stirrer is put into motion, a solution of 53.7 g. (0.2 moles) of l-dodecylcyclohexane-l-ol in 60 ml. of abs. benzene is added dropwise to the mixture, then the reaction mixture is refluxed for 2 hours. Thereafter a solution of 25.96 g. (0.22 moles) of propargyl bromide in 50 ml. of abs. benzene are added drop-wise into the mixture, and the reaction mixture is refluxed for further 6 hours.

Thereafter the mixture is cooled to room temperature, washed with 2X50 ml. of water. the solvent is evaporated in vacuo, and the residue is fractionally distilled in VklCLlO. Yield: 46 g. (75 Bp.: l74178C/0.6 mm.Hg. The product is a pale yellow oil.

EXAMPLE 2 l-( 2 4-Dichlorophenyl.)- l-( 3 "propargyloxy cyclohexane The process described in Example 1 is repeated with EXAMPLE 3 i l-(2, 3 -Dichlorophenyl l 3 -propargyloxy)-cyclohexane One proceeds as described in Example 1, with the difference, that 1-dodecyl-cyclohexane-l-ol is replaced by 49 g. (0.2 moles) of 1-(2, 3'-dichlorophenyl)-' cyclohexane-l-ol. The product is obtained with a yield of 34.5 g. (62.2 Bp.: 169174C/7 mmgHg.

' EXAMPLE 4 1-(3, 4-Dichlorophenyll 3 -propargyloxy )-cyclohexane One proceeds as described in Example 1, with the difference, that l-dodecyl-cyclohexane-l-ol is replaced by 30 g. (0.122 moles) of 1-(3, 4-diehlorophenyl)- cyclohexane-l-ol. The product is obtained with a yield of 23.3 g. (67.4 Bp.: 179l84C/6 mm.Hg.

EXAMPLE 5 l-( p-Chlorophenyl l 3 -propargyloxy )-cyclohexane EXAMPLE 6 l-Benzyll 3 -propargyloxy) cycloheptane One proceeds as described in Example 1, with the difference, that l-dodecyl-cyclohexane- 1 -ol is replaced by 61.2 g. (0.3 moles) of l-benzyl-cycloheptane-l-ol. The pale yellow. viscous product is obtained with a yield of 40.2 g. (33 Bp.: 156l6lC/5.5 mm.Hg.

EXAMPLE 7 l-Benzyll 3 'propargyloxy )-cylopentane One proceeds as described in Example 1, with the difference, that l-dodecyl-cyclohexane-l-ol is replaced the difference that l-dodecyl-cyclohexane-l-ol is re- 7 placed by 49 g. (0.2 moles) of 1-(2'.4- dichlorophenyl)-cyclohexane-l-ol.The product is a slowly crystallizing, pale yellow, viscous oil. Yield: 42.4 g. (75.5 Bp.: l74l78C/6.5 mm.Hg.

by 49 g. (0.279 moles)'of l-benzyl-cyclopentane-l-ol. The pale yellow, viscous product is obtained with a yield of 40 g. (68 Bp.: l32-l40C/6 mm.Hg.

EXAMPLE 8 l-Dodecyll-( 3 '-propargyloxy cyclohexane One proceeds as described in Example 1, with the difference, that 4.6 g. (0.2 moles) of sodium dispersion is used in the preparation of the alcoholate in the place of sodium amide. The cessation of the hydrogen evolution indicates the termination of the reaction. The product is obtained with a yield identical to that described in Example 1. The physical data of the compound are also identical to that listed in Example 1.

EXAMPLE 9 l-Benzyll-[4'-( l "-methyl-4"-piperazinyl )-butyn- (2 )-yl-oxy l-cycloheptane difumarate 38.45 g. (0.1585 moles) of l-benzyl-l-(3'-propargyloxy)-cycloheptane, 40 ml. of dioxane, 17.5 g. of N-mcthylpiperazine, 5.8 g. of paraformaldehyde and 0.3 g. of cupric acetate are introduced into a 250 ml. three-necked flask equipped with a stirrer and a reflux condenser. The mixture is stirred and refluxed for 3 hours, thereafter it is cooled to room temperature and poured into 200 ml. of water. The mixture is extracted three times with 100 ml. portions of benzene. The benzene solutions are combined, decolourized with carbon, filtered, and evaporated on a hot water bath. 48 g. (86.5 of the product are obtained.

The obtained base is reacted with calculated amount of fumaric acid to yield the fumarate salt, m.p.: 174.9 C.

Analysis: C H N O Calculated C 63.46; H 7.21; N 4.77.

Found C 63.46; H 7.58; N 4.75.

EXAMPLE l l-Heptyll 3 '-propargyloxy )-cycloheptane One proceeds as described in Example 1, with the difference, that l-dodecyl-cyclohexane- 1 -01 is replaced with 42.4 g. (0.2 moles) of l-heptyl-cycloheptane-l o1. 38.4 g. (76.8 of a pale yellow, oily product are obtained. B.p.: 115120C/0.3 mm.Hg.

EXAMPLE 1 1 Di-[ l-heptyl-1-(4-/l"-B-hydroxyethyl4 piperazinyl butyn-/2/-yl-oxy )-cyclohexane trifumarate One proceeds as described in Example 9, with the difference, that the following compounds are used as starting substances: 25 g. (0.1 moles) of l-hepty1-1-(3- propyloxy)-cycloheptane. 25 ml. of dioxane. 14.3 g. of N-B-hydroxyethyl-piperazine, 3.6 g. of paraformaldehyde and 0.2 g. of cupric acetate. 33.2 g. (84.6 70) of the base are obtained. The base is converted into its fumarate melting at l23l25C. Results of titration in non-aqueous medium:

base content: 98.9 "/1 acid content: 99.2 "/1.

EXAMPLE 12 EXAMPLE 13 l-Benzyl- 1-[ 4'-( l "-B-hydroxyethyl-4"-piperaziny1)- butyn( 2 )-yl-oxy l-cyclopentane monofumarate A mixture of 21.4 g. (0.1 moles) of l-benzyl-l-(3- propargyloxyl-eyelopentane, 25 ml. of dioxane, 14.3 g. of N-B-hydroxyethyl-piperazine, 3.6 g. of paraformaldehyde and 0.2 g. of cupric acetate is reacted as de scribed in Example 9. 28.1 g. (77.9 '7() of the free base are obtained. The fumarate salt melts at 137C.

Analysis: C H N O...

Calculated 7!: C 65.38; H 8.65; N 5.86.

Found '71: C 65.3: H 8.57; N 5.82.

EXAMPLE l4 1-(3', 4'-Dichlorophenyl)-l-[4'-( 1 -B-hydroxyethyl-4"- piperazinyl )-butyn-( 2) -yl-oxy]-cyclohexane difumarate A mixture of 23.3 g. (0.0823 moles) of 1-(3, 4- dichlorophenyl l 3 -pro'pa:rgyloxy )-cyclohexane, 25 ml. of dioxane, 1 1.8 g. of N-B-hydroxyethyl-piperazine, 2.96 g. of paraformaldehyde and 0.2 g. of cupric acetate is reacted as described in Example 9. 29.7 (85 of the free base are obtained. The fumarate salt melts at 198.5C.

Analysis: C H Cl N O Calculated C 54.8; H 5.82; Cl 10.78; N 4.26.

Found C 54.54; H 5.99; Cl 10.9; N 4.4

EXAMPLE l5 1-(p-Chloropheny1)-l-[4'-( l "-methyl-4- piperazinyl )-butyn-( 2 )-yl-0xy ]-cyclohexane difumarate A mixture of 24.8 g. (0.1 moles) of l-(pchlorophenyl 1 3 -propargyloxy )-cyclohexane, 25 ml. of dioxane, l 1 g. of N-me'thyl-piperazine, 3.6 g. of paraformaldehyde and 0.2 g. of cupric acetate is reacted as described in Example 9. The free base is obtained with a yield of 32.6 g. (90.5 The fumarate melts at 184.3C.

Analysis: C H CIN O Calculated C 58.73; H 6.29; CI 5.97; N 4.72.

Found /r: C 58.6; H 6.37; C1 5.9; N 4.64.

EXAMPLE l6 Di-[ 1-dodecy1-1-(4-/l "-i8-hydroxyethyl-4"- piperazinyl/-butyn-/2/-yloxy)-cyelohexane]- trifumarate A-mixture of 46 g. (0.15 moles) of l-dodecyl-l-(3- propargyloxy)-cyclohexane, 45 m1. of dioxane, 21.5 g. of N-B-hydroxyethyl-piperazin, 5.4 g. of paraformaldehyde and 0.3 g. of cupric acetate is reacted as described in Example 9. The free base is obtained with a yield of 54.3 g. (81 70). The fumarate melts at 136.4 C.

Results of titration in non-aqueous medium:

base content: 99.7

acid content: 98.7

EXAMPLE l7 1 2 3 -Dichlorophenyl 1 -[4"-( l "-B-hydroxyethy1-4"- piperazinyl.)-butyn-( 2 )-yl-oxy ]-cyelohexane fumarate A mixture of 17.2 g. (0.()608 moles) of 1-(2, 3'- dichlorophenyl 1-( 3 -propargyloxy )-cyc1ohexane. 16 m1. of dioxanc. 8.7 g. of N-B-hydroxyethyl-piperazine, 2.18 g. of paraformaldehyde and 0.15 g. of cupric acetate is reacted as described in Example 9. 21.1 g. (81.5 71) of the free base are obtained. The fumarate melts at 166C.

Analysis: C ,;H C1 N O Calculated 7r: C 54.8; H 5.82; Cl 10.78; N 4.26.

Found 7(: C 54.75; H 5.75; Cl 10.8; N 4.2.

EXAMPLE 1 8 2 I 4-Dichlorophenyl)-1-[4'-( l "-B-hydroxyethyl-4"- piperazinyl )butyn-( 2 )-yl-oxy]-cyclohexane monofumarate A mixture of 11.8 g. (0.0418 moles) of 1(2. 4- dich1oropheny1)-1-( 3"propargyloxy)-cyclohexane. 1 1 ml. of dioxane, 1.5 g. of paraformaldehyde. 6 g. of N-B-hydroxyethyl-piperazine and 0.1 g. of cupric acetate is reacted as described in Example 9. The free base is obtained with a yield of l 1 g. (61.5 70 The fumarate melts at 159.6C.

Results of titration in nonaqueous medium:

base content: 991% acid content: 98.7

EXAMPLE l9 EXAMPLE 20 l-(pChlorophenyl)-1-/4'-( l "-/3-hydroxyethyl-4"- piperazinyl)-butoxyl-cyclohexane difumaratc 10 g. of l-(p-chlorophenyl)l-[ 4'-( 1-B- hydroxyethyl-4' '-piperazinyl )-butyn( 2 )yl-oxy cyclohexane base (prepared as described in Example 12) are dissolved in 30 ml. of ethanol. 1 g. of palladium-on-carbon are added to the solution, and the mixture is hydrogenated at room temperature. When the hydrogen uptake ceases, the catalyst is removed by filtration, and the obtained base is converted to the difumarate preferably in the reaction medium itself. The fumarate salt melts at 191.3 C.

Analysis: C H clN O Calculated C 57.46; H 691; Cl 5.65; N 4.47.

Found "/r: C 57.52; H 7.1; Cl 5.75; N 4.51.

EXAMPLE 21 1Benzyll 4'-( 1 '-,B-hydroxyethyl-4' -piperazinyl butyn-( 2 )-yl-oxy l-cycloheptane difumarate A mixture of 38.45 g. (0.1585 moles) of l-benzyl-l- (3'-propargyloxy)-cycloheptane, 40 ml. of dioxane, 22.7 g. of N-B-hydroxyethyl-piperazine. 5.7 g. of paraformaldehyde and 0.31 g. of cupric acetate is reacted as described in Example 9. The free baseis obtained with a yield of 47.9 g. (79 71). The fumarate melts at 181C.

Analysis: C H N- O Calculated C 62.31; H 7.19; N 4.54.

Found "/z: C. 62.2; H 7.2; N 4.58.

EXAMPLE 22 Di-[1-(p-chlorophenyl)-l-(3",4,5- trimethoxybenzoyl-4-/ 1 -B-hydroxyethyl-4 piperazinyl/butyn-/2/-y1-oxy )-cyclohexane trifumarate 10 g. (0.0256 moles) of 1-(p-chlorophenyl)-1-[4- l "-,8-hydroxyethyl-4"-piperazinyl)-butyn-(2)-yl oxyI-cyelohexane (prepared as described in Example 12) are dissolved in 50 ml. of dichloroethane. and 5.93 g. of 3.4,5-trimethoxybenzoylchloride are added to the solution with stirring. After theaddition is complete, the mixture is stirred at room temperature for 4 hours, thereafter it is washed with 20 ml. of saturated aqueous sodium carbonate solution. The solution is dried and evaporated to dryness in vacuo. The free base is obtained with a yield of 14.9 g. (98.5 The fumarate melts at 156.5C.

Results of titration in nonaqueous medium:

base content: 98.5

acid content: 9875 EXAMPLE 23 DH l-Benzyl-1-(3",4",5"-trimethoxybenzoyl-4'-/l B-hydroxyethyl4' '-piperazinyl/butyn-/2/-yl-oxy cycloheptane ltrifumarate.

A mixture of 10 g. (0.0261 moles) of 1-benzyl-1-[4'- 1 "-,8-hydroxyethyl-4"-piperazinyl )-butyn-( 2)-yloxy]cyc1oheptane (prepared as described in Example 21 50 ml. of dichloroethane and 6.2 g. of 3.4.5- trimethoxybenzoylchloride is reacted as described in Example 20. The free base is obtained with a yield of 14.2 g. (94.5 71). The fumarate melts at 144.3C.

Results of titration in nonaqueous medium:

base content: 100.1 '71 acid content: 99.8 /r

EXAMPLE 24 1-( p-Chlorophenyl 1-[4-( 1 -methyl-4- piperazinyl )-butyn-(2)-yl-oxy]-cyc1ohexane difumarate A solution of 21 g. (0.1 moles) of l-(pchlorophenyl)-cyclohexane-1-ol in 30 ml. of abs. benzene is added dropwise, with intensive stirring to a suspension of 3.9 g. (0.1 moles) of powdery sodium amide in 30 ml. of abs. benzene, and the mixture is refluxed for 2 hours. Thereafter a solution of 20.5 g. of 1- methyl-4-[4'-chloro-butyn-(2)-yl]-piperazine in 30 ml. of abs. benzene is added to the mixture, and the mixture is refluxed for further 6 hours. The resulting mixture is washed three times with 20 ml. portions of water. and evaporated to dryness in vacuo. 18.8 g. (52 7( of the free base are obtained as a residue. The fumarate melts at 184.3C. The physical constants of the fumarate are identical to that indicated in Example 15.

EXAMPLE 25 Di-l 1-dodecyll-(4 /1"-B-hydroxyethyl-4"- piperazinyll/-butyn-/2/-yl-oxy)-cyclohexane] trifumaratc A Grignard compound is prepared from 15.62 g. (0.11 moles) of methyl iodide and 2.68 g. (0.11 g.- atom) of magnesium in m1. of abs. ether. thereafter a solution of 30.65 g. (01 moles) of 1-dodecyl-1-(3- propargyloxy)cyclohexane in 50 ml. of abs. ether are added to the Grignard reagent. The reaction mixture is boiled until the gas evolution ceases. then 3 g. (0.] moles) of trioxymethylene (or gaseous formaldehyde) are added to the mixturev The mixture is boiled for further 4 hours, then it is added to a solution of g. of ammonium chloride in 40 ml. of ice water. The etheral phase is separated, dried and evaporated. The oily residue is purified by vacuum distillation. The boiling point of the product is 202C/().6 mmHg. According to an other method of purification, the crude product is reacted with a suspension of 3.9 g. (0.] moles) of sodium amide in 60 ml. of absv benzene, and when the ammonia evolution ceases, the mixture is cooled to a temperature below C and 19 g. (0.1 moles) of tosyl chloride are added to it. The mixture is stirred for several hours at room temperature, thereafter it is washed successively with ml. of water, 30 ml. of saturated aqueous sodium hydrocarbonate solution and again with 30 ml. of water. The benzene solution is dried, then 13 g. of N-B-hydroxyethyl-piperazine are added to it, and the mixture is heated to boiling. The mixture is washed with saturated aqueous sodium hydrocarbonate solution and with water, dried, and evaporated to dryness in vacuo. The product is obtained with a yield of 39 g. (87 7t The fumarate melts 136.4l 36 C. The product is identical to the compound obtained according to M Example l6.

What we claim is: l. A cyeloalkanol ether of the formula monohalophenyl or 

1. A CYCLOALKANOL ETHER OF THE FORMULA
 2. Di-(1-dodecyl-1-(4''-/1''''- Beta -hydroxyethyl-4''''-piperazinyl/-butyn-/2/-yl-oxy)-cyclohexane)-trifumarate according to claim
 1. 